Since elucidation of its structure in 1981, corticotropin-releasing factor (CRF), a neuropeptide comprised of 41 amino acids, has been shown to function as a hypothalamic releasing hormone by regulating the secretion of corticotropin (ACTH) and other pro- opiomelanocortin-related peptides from the anterior pituitary. The heterogeneous distribution of CRF and CRF receptors in hypothalamic and extrahypothalamic regions of the mammalian CNS, and its electrophysiological and behavioral effects, all are concordant with an extra-endocrine role for this peptide in higher brain centers. The present proposal seeks to utilize preclinical and clinical paradigms to provide further evidence for a role for CRF as a neurotransmitter in the CNS, and furthermore, to investigate the hypothesis that CRF is hypersecreted in patients with major depression. Towards the former goal, we shall elucidate CRF-containing neural circuits in the rat CNS by a combination of chemical lesioning techniques and use of a sensitive and specific radioimmunoassay for the peptide, determine what neurotransmitters/neuromodulators regulate CRF release, determine the subcellular distribution of CRF, determine whether cyclic nucleotides mediate CRF responses in the CNS and finally, determine the role of CRF neurons in responses to acute and chronic stress. Towards the latter goal, we shall attempt to confirm and extend our previous findings that cerebrospinal fluid (CSF) concentrations of CRF are elevated in patients with major depression by studying a large population of well-characterized, drug-free neuropsychiatric patients. The specificity of this finding will be studied by measurement of CSF CRF, not only in patients with major depression, but also in schizophrenic and demented patients, as well as patients with Huntington's chorea and multiple sclerosis. We shall determine whether the elevation in CSF CRF-L1 is state-dependent by: 1) determining whether treatment with electroconvulsive therapy (ECT) produces a significant reduction in CSF CRF-L1, and, 2) determining whether treatment with tricyclic antidepressants in multiple sclerosis patients with depression results in a reduction in CSF CRF-L1. Finally, the specificity of the blunted ACTH response to intravenously (IV)-administered CRF in depressed patients will be explored. We shall study patients not only with major depression, but also those with diagnoses of schizophrenia, post- traumatic stress disorder and panic disorder, resulting in novel information on the role of CRF in affective disorders.